Introduction to Immunology PDF

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Introduction to Immunology...

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Introduction to Immunology Contents 1 Introduction 2 Self and Nonself 3 The Structure of the Immune System 7 Immune Cells and Their Products 19 Mounting an Immune Response 24 Immunity: Natural and Acquired 28 Disorders of the Immune System 34 Immunology and Transplants 36 Immunity and Cancer 39 The Immune System and the Nervous System 40 Frontiers in Immunology 45 Summary 47 Glossary

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Introduction The immune system is a network of cells, tissues*, and organs that work together to defend the body against attacks by “foreign” invaders. These are primarily microbes (germs)—tiny, infection-causing organisms such as bacteria, viruses, parasites, and fungi. Because the human body provides an ideal environment for many microbes, they try to break in. It is the immune system’s job to keep them out or, failing that, to seek out and destroy them. When the immune system hits the wrong target or is crippled, however, it can unleash a torrent of diseases, including allergy, arthritis, or AIDS. The immune system is amazingly complex. It can recognize and remember millions of different enemies, and it can produce secretions and cells to match up with and wipe out each one of them. The secret to its success is an elaborate and dynamic communications network. Millions and millions of cells, organized into sets and subsets, gather like clouds of bees swarming around a hive and pass information back and forth. Once immune cells receive the alarm, they undergo tactical changes and begin to produce powerful chemicals. These substances allow the cells to regulate their own growth and behavior, enlist their fellows, and direct new recruits to trouble spots. Self and Nonself The key to a healthy immune system is its remarkable ability to distinguish between the body’s own cells—self—and foreign cells—nonself. The body’s immune defenses normally coexist peacefully with cells that carry distinctive “self” marker molecules. But when immune defenders encounter cells or

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organisms carrying markers that say “foreign,” they quickly launch an attack. Anything that can trigger this immune response is called an antigen. An antigen can be a microbe such as a virus, or even a part of a microbe. Tissues or cells from another person (except an identical twin) also carry nonself markers and act as antigens. This explains why tissue transplants may be rejected. In abnormal situations, the immune system can mistake self for nonself and launch an attack against the body’s own cells or tissues. The result is called an autoimmune disease. Some forms of arthritis and diabetes are autoimmune diseases. In other cases, the immune system responds to a seemingly harmless foreign substance such as ragweed pollen. The result is allergy, and this kind of antigen is called an allergen. The Structure of the Immune System The organs of the immune system are positioned throughout the body. They are called lymphoid organs because they are home to lymphocytes, small white blood cells that are the key players in the immune system.

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The organs of the immune system are positioned throughout the body. Bone marrow, the soft tissue in the hollow center of bones, is the ultimate source of all blood cells, including white blood cells destined to become immune cells. The thymus is an organ that lies behind the breast bone; lymphocytes known as T lymphocytes, or just “T cells,” mature in the thymus.

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The lymph node contains numerous specialized structures. T cells concentrate in the paracortex, B cells in and around the germinal centers, and plasma cells in the medulla. Lymphocytes can travel throughout the body using the blood vessels. The cells can also travel through a system of lymphatic vessels that closely parallels the body’s veins and arteries. Cells and fluids are exchanged between blood and lymphatic vessels, enabling the lymphatic system to monitor the body for invading microbes. The lymphatic vessels carry lymph, a clear fluid that bathes the body’s tissues. Small, bean-shaped lymph nodes are laced along the lymphatic vessels, with clusters in the neck, armpits, abdomen, and groin. Each lymph node contains specialized compartments where immune cells congregate, and where they can encounter antigens. Immune cells and foreign particles enter the lymph nodes via incoming lymphatic vessels or the lymph nodes’ tiny blood vessels. All lymphocytes exit lymph nodes through outgoing lymphatic vessels. Once in the bloodstream, they are transported to tissues throughout the body. They patrol

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everywhere for foreign antigens, then gradually drift back into the lymphatic system, to begin the cycle all over again. The spleen is a flattened organ at the upper left of the abdomen. Like the lymph nodes, the spleen contains specialized compartments where immune cells gather and work, and serves as a meeting ground where immune defenses confront antigens. Clumps of lymphoid tissue are found in many parts of the body, especially in the linings of the digestive tract and the airways and lungs—territories that serve as gateways to the body. These tissues include the tonsils, adenoids, and appendix.

Lymphatic vessel Immune cells and foreign particles enter the lymph nodes via incoming lymphatic vessels or the lymph nodes’ tiny blood vessels. Immune Cells and Their Products The immune system stockpiles a huge arsenal of cells, not only lymphocytes but also cell-devouring phagocytes and their relatives. Some immune cells take on all comers, while others are trained on highly specific targets. To work effectively, most

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immune cells need the cooperation of their comrades. Sometimes immune cells communicate by direct physical contact, sometimes by releasing chemical messengers. The immune system stores just a few of each kind of the different cells needed to recognize millions of possible enemies. When an antigen appears, those few matching cells multiply into a full-scale army. After their job is done, they fade

An antibody is made up of two heavy chains and two light chains. The variable region, which differs from one antibody to the next, allows an antibody to recognize its matching antigen. away, leaving sentries behind to watch for future attacks. All immune cells begin as immature stem cells in the bone marrow. They respond to different cytokines and other signals to grow into specific immune cell types, such as T cells, B cells, or phagocytes. Because stem cells have not yet committed to a particular future, they are an interesting possibility for treating some immune system disorders. Researchers currently are investigating if a person’s own stem cells can be used to regenerate damaged immune responses in autoimmune diseases 7

and immune deficiency diseases. B Lymphocytes B cells and T cells are the main types of lymphocytes. B cells work chiefly by secreting substances called antibodies into the body’s fluids. Antibodies ambush antigens circulating the bloodstream. They are powerless, however, to penetrate cells. The job of attacking target cells—either cells that have been infected by viruses or cells that have been distorted by cancer—is left to T cells or other immune cells (described below).

B cells mature into plasma cells that produce antibodies. Each B cell is programmed to make one specific antibody. For example, one B cell will make an antibody that blocks a virus that causes the common cold, while another produces an antibody that attacks a bacterium that causes pneumonia. When a B cell encounters its triggering antigen, it gives rise to many large cells known as plasma cells. Every plasma cell is essentially a factory for producing an antibody. Each of the plasma cells descended from a given B cell manufactures 8

millions of identical antibody molecules and pours them into the bloodstream. An antigen matches an antibody much as a key matches a lock. Some match exactly; others fit more like a skeleton key. But whenever antigen and antibody interlock, the antibody marks the antigen for destruction.

Immunoglobulins Antibodies belong to a family of large molecules known as immunoglobulins. Different types play different roles in the immune defense strategy. • Immunoglobulin G, or IgG, works efficiently to coat microbes, speeding their uptake by other cells in the immune system. • IgM is very effective at killing bacteria. • IgA concentrates in body fluids—tears, saliva, the secretions of the respiratory tract and the digestive tract—guarding the entrances to the body.

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• IgE, whose natural job probably is to protect against parasitic infections, is the villain responsible for the symptoms of allergy. • IgD remains attached to B cells and plays a key role in initiating early B-cell response. T Cells Unlike B cells, T cells do not recognize free-floating antigens. Rather, their surfaces contain specialized antibody-like receptors that see fragments of antigens on the surfaces of infected or cancerous cells. T cells contribute to immune defenses in two major ways: some direct and regulate immune responses; others directly attack infected or cancerous cells. Helper T cells, or Th cells, coordinate immune responses by communicating with other cells. Some stimulate nearby B cells to produce antibody, others call in microbe-gobbling cells called phagocytes, still others activate other T cells. Killer T cells—also called cytotoxic T lymphocytes or CTLs— perform a different function. These cells directly attack other cells carrying certain foreign or abnormal molecules on their surfaces. CTLs are especially useful for attacking viruses because viruses often hide from other parts of the immune system while they grow inside infected cells. CTLs recognize small fragments of these viruses peeking out from the cell membrane and launch an attack to kill the cell.

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Some T cells are helper cells, others are killer cells.

Killer cell makes contact with target cell, trains its weapons on

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the target, then strikes. In most cases, T cells only recognize an antigen if it is carried on the surface of a cell by one of the body’s own MHC, or major histocompatibility complex, molecules. MHC molecules are proteins recognized by T cells when distinguishing between self and nonself. A self MHC molecule provides a recognizable scaffolding to present a foreign antigen to the T cell. Although MHC molecules are required for T-cell responses against foreign invaders, they also pose a difficulty during organ transplantations. Virtually every cell in the body is covered with MHC proteins, but each person has a different set of these proteins on his or her cells. If a T cell recognizes a nonself MHC molecule on another cell, it will destroy the cell. Therefore, doctors must match organ recipients with donors who have the closest MHC makeup. Otherwise the recipient’s T cells will likely attack the transplanted organ, leading to graft rejection. Natural killer (NK) cells are another kind of lethal white cell, or lymphocyte. Like killer T cells, NK cells are armed with granules filled with potent chemicals. But while killer T cells look for antigen fragments bound to self-MHC molecules, NK cells recognize cells lacking self-MHC molecules. Thus NK cells have the potential to attack many types of foreign cells.

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Phagocytes, granulocytes, and mast cells, all with different methods of attack, demonstrate the immune system’s versatility. Both kinds of killer cells slay on contact. The deadly assassins bind to their targets, aim their weapons, and then deliver a lethal burst of chemicals. Phagocytes and Their Relatives Phagocytes are large white cells that can swallow and digest microbes and other foreign particles. Monocytes are phagocytes that circulate in the blood. When monocytes migrate into tissues, they develop into macrophages. Specialized types of macrophages can be found in many organs, including lungs, kidneys, brain, and liver. Macrophages play many roles. As scavengers, they rid the body of worn-out cells and other debris. They display bits of foreign antigen in a way that draws the attention of matching lymphocytes. And they churn out an amazing variety of powerful chemical signals, known as monokines, which are vital to the immune responses.

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Granulocytes are another kind of immune cell. They contain granules filled with potent chemicals, which allow the granulocytes to destroy microorganisms. Some of these chemicals, such as histamine, also contribute to inflammation and allergy. One type of granulocyte, the neutrophil, is also a phagocyte; it uses its prepackaged chemicals to break down the microbes it ingests. Eosinophils and basophils are granulocytes that “degranulate,” spraying their chemicals onto harmful cells or microbes nearby. The mast cell is a twin of the basophil, except that it is not a blood cell. Rather, it is found in the lungs, skin, tongue, and linings of the nose and intestinal tract, where it is responsible for the symptoms of allergy. A related structure, the blood platelet, is a cell fragment. Platelets, too, contain granules. In addition to promoting blood clotting and wound repair, platelets activate some of the immune defenses. Cytokines Components of the immune system communicate with one another by exchanging chemical messengers called cytokines. These proteins are secreted by cells and act on other cells to coordinate an appropriate immune response. Cytokines include a diverse assortment of interleukins, interferons, and growth factors. Some cytokines are chemical switches that turn certain immune cell types on and off. One cytokine, interleukin 2 (IL-2), triggers the immune system to produce T cells. IL-2’s immunity-boosting properties have traditionally made it a promising treatment for several illnesses.

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Clinical studies are ongoing to test its benefits in other diseases such as cancer, hepatitis C, and

Cytokines include lymphokines, produced by lymphocytes, and monokines, made by monocytes and macrophages. HIV infection and AIDS. Other cytokines also are being studied for their potential clinical benefit. Other cytokines chemically attract specific cell types. These socalled chemokines are released by cells at a site of injury or infection and call other immune cells to the region to help repair the damage or fight off the invader. Chemokines often play a key role in inflammation and are a promising target for new drugs to help regulate immune responses. Complement The complement system is made up of about 25 proteins that work together to “complement” the action of antibodies in destroying bacteria. Complement also helps to rid the body of antibody-coated antigens (antigen-antibody complexes). Complement proteins, which cause blood vessels to become dilated and then leaky, contribute to the redness, warmth, swelling, pain, and loss of function that characterize an 15

inflammatory response. Complement proteins circulate in the blood in an inactive form. When the first protein in the complement series is activated— typically by antibody that has locked onto an antigen—it sets in motion a domino effect. Each component takes its turn in a precise chain of steps known as the complement cascade. The end product is a

The interlocking steps of the complement cascade end in cell death. cylinder inserted into—and puncturing a hole in—the cell’s wall. With fluids and molecules flowing in and out, the cell

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swells and bursts. Other components of the complement system make bacteria more susceptible to phagocytosis or beckon other cells to the area. Mounting an Immune Response Infections are the most common cause of human disease. They range from the common cold to debilitating conditions like chronic hepatitis to life-threatening diseases such as AIDS. Disease-causing microbes (pathogens) attempting to get into the body must first move past the body’s external armor, usually the skin or cells lining the body’s internal passageways. The skin provides an imposing barrier to invading microbes. It is generally penetrable only through cuts or tiny abrasions. The digestive and respiratory tracts—both portals of entry for a number of microbes—also have their own levels of protection. Microbes entering the nose often cause the nasal surfaces to secrete more protective mucus, and attempts to enter the nose or lungs can trigger a sneeze or cough reflex to force microbial invaders out of the respiratory passageways. The stomach contains a strong acid that destroys many pathogens that are swallowed with food.

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When challenged, the immune system has many weapons to choose. If microbes survive the body’s front-line defenses, they still have to find a way through the walls of the digestive, respiratory, or urogenital passageways to the underlying cells. These passageways are lined with tightly packed epithelial cells covered in a layer of mucus, effectively blocking the transport of many organisms. Mucosal surfaces also secrete a special class of antibody called IgA, which in many cases is the first type of antibody to encounter an invading microbe. Underneath the epithelial layer a number of cells, including macrophages, B cells, and T cells, lie in wait for any germ that might bypass the barriers at the surface. Next, invaders must escape a series of general defenses, which are ready to attack, without regard for specific antigen markers. These include patrolling phagocytes, NK cells, and complement. Microbes that cross the general barriers then confront specific

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weapons tailored just for them. Specific weapons, which include both antibodies and T cells, are equipped with singular receptor structures that allow them to recognize and interact with their designated targets. Bacteria, Viruses, and Parasites The most common disease-causing microbes are bacteria, viruses, and parasites. Each uses a different tactic to infect a person, and, therefore, each is thwarted by a different part of the immune system. Most bacteria live in the spaces between cells and are readily attacked by antibodies. When antibodies attach to a bacterium, they send signals to complement proteins and phagocytic cells to destroy the bound microbes. Some bacteria are eaten directly by phagocytes, which signal to certain T cells to join the attack. All viruses, plus a few types of bacteria and parasites, must enter cells to survive, requiring a different approach. Infected cells use their MHC molecules to put pieces of the invading microbes on the cell’s surface, flagging down cytotoxic T lymphocytes to destroy the infected cell. Antibodies also can assist in the immune response, attaching to and clearing viruses before they have a chance to enter the cell.

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Parasites live either inside or outside cells. Intracellular parasites such as the organism that causes malaria can trigger Tcell responses. Extracellular parasites are often much larger than bacteria or viruses and require a much broader immune attack. Parasitic infections often trigger an inflammatory response 21

when eosinophils, basophils, and other specialized granular cells rush to the scene and release their stores of toxic chemicals in an attempt to destroy the invader. Antibodies also play a role in this attack, attracting the granular cells to the site of infection. Immunity: Natural and Acquired Long ago, physicians realized that people who had recovered from the plague would never get it again—they had acquired immunity. This is because some of the activated T and B cells become memory cells. The next time an individual meets up with the same antigen, the immune system is set to demolish it. Immunity can be strong or weak, shortlived or long-lasting, depending on the type of antigen, the amount of antigen, and the route by which it enters the body.

Immunity can also be influenced by inherited genes. When faced with the same antigen, some individuals will respond forcefully, others feebly, and some not at all.
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